Schistosomiasis is an important tropical parasitic disease with more than two hundred million human infections in more than 70 countries. The mortality due to schistosome infections in sub-Saharan Africa is estimated to be 280,000 per year and an additional 20 million individuals suffer severe disease symptoms. Currently, drug treatment is based on a single agent, praziquantel, and there is evidence supporting the emergence of drug resistant parasites. Because no suitable alternative therapy or vaccine is available, there is an urgent need for the development of novel chemotherapeutic agents and vaccines. More detailed information about the basic biology of schistosomes will facilitate vaccine and novel drug design. We suggest that identification of factors controlling worm development and sexual differentiation in the mammalian host will provide new targets for drugs and vaccines. Examination of genome-wide gene expression patterns in worms during development in the mammalian host will provide a coherent picture of schistosome biological pathways that influence parasite adaptation to the host environment. We propose to utilize Serial Analysis of Gene Expression (SAGE) to monitor genome-wide levels of mRNA expression during parasite development and sexual differentiation. To detect differential transcription of genes related to development, we will perform SAGE by generating ~75,000 20 bp sequence tags from the mRNA isolated from cercariae, schistosomula, immature worms, sexually mature and virgin worms, and eggs. SAGE is ideal to investigate global gene expression during parasite development and sexual differentiation. This research will lead to the identification of novel genes expressed during development and sexual differentiation and that allow the parasite to evade the immune response and persist in the mammalian host. As genome sequencing of Schistosoma mansoni is nearly complete, functional genomic studies will be essential to capitalize on the massive genomic database being generated. SAGE analysis will complement the ongoing annotation of the S. mansoni genome and studies using DNA micro arrays. Furthermore, we will validate the use of SAGE technology to study differential global gene expression in S. mansoni.